There is a rapidly increasing basic and clinical interest in a better understanding of atrial natriuretic factor (ANF) secretion in pulmonary hypertension. High levels of ANF correlate with pulmonary hypertension during hypoxia and exercise, and in patients with angina pectoris, heart disease, ventricular septal defects, and respiratory distress. ANF release is important in these situations, because ANF is a potent pulmonary vasorelaxant, and could reduce the right ventricular afterload and risks of right heart failure. The mechanisms of the ANF release, however, are poorly understood. Pilot studies suggest that a neural reflex of pulmonary arterial origin mediates the ANF response to pulmonary hypertension, and half the ANF response to hypoxia. An arterial chemoreceptor reflex may mediate the remaining ANF response to hypoxia. The proposed experiments will elucidate, for the first time, the role of these neural reflexes in the control of ANF release. All experiments will be performed on anesthetized, artificially ventilated, fully instrumented pigs. Blood samples will be continuously withdrawn to determine the plasma ANF concentrations. Aim 1 of the research program is to test whether pulmonary arterial stretch receptors with vagal afferents form the afferent limb, and the sympathetic outflow the efferent limb of a novel ANF-releasing reflex. Pulmonary hypertension will be induced by intravenous air infusion and by hypoxia. The pulmonary artery, cervical vagi, stellate cardiac nerves, or adrenal medullae will be locally anesthetized to identify the critical neural structures involved. By measuring, in addition, the ANF response to autonomic nerve stimulation, the afferent and efferent limbs of this reflex can be unequivocally determined. Aim 2 of the research program is to test whether carotid chemoreceptors stimulate the release of ANF, by challenging the carotid chemoreceptors with buffer or blood equilibrated at low P02. By reversibly blocking the autonomic nerves, the efferent limb of this new reflex will be elucidated. To show whether carotid chemoreceptors are physiologically involved in the ANF response, the carotid chemoreceptors will be exposed to normoxic blood during alveolar hypoxia. The results will add fundamental new information on the stimulus-secretion coupling in atrial myocytes. They will also provide a better understanding of potential ANF release mechanisms in patients with cardio-pulmonary disease.